Epilepsy is the third most common chronic neurological disorder, affecting 2.5 million persons in the USA. Temporal lobe epilepsy (TLE), with seizures involving the hippocampal circuit, is one of the most severe epilepsies in adults, and is refractory to medical treatment in >30% of individuals. TLE is commonly preceded by febrile status epilepticus (FSE). Whereas the relationship of FSE to human TLE is not fully understood, experimental FSE provokes TLE in animal models, suggesting that FSE might contribute to epileptogenesis in both normal and predisposed brain. Importantly, the contribution of FSE to TLE (as a 1st or 2nd hit) may be predictable and preventable. TLE commonly affects the young, exacting a tremendous toll on human potential. However, there are major challenges in preventing or aborting TLE: (1) We do not know the mechanisms for the contribution of FSE to TLE; (2) We do not have predictive markers to identify the 30-40% of those experiencing FSE who will proceed to develop TLE; (3) We do not have mechanism-based drugs to abort the epileptogenic process that bridges FSE and TLE. The three specific aims of this competing renewal proposal address these major challenges. We capitalize on results obtained during the current award period, on our published and novel findings regarding the molecular, cellular and network changes that follow FSE and contribute to epileptogenesis, and on exciting data supporting clinically-translatable predictive markers. We employ innovative methods in in vitro and in vivo systems, and integrate hypothesis-driven and large scale gene expression analyses. We devise innovative decoy and mimic approaches for both probing mechanistic questions and for potential translation. Our work to date has revolutionized the scientific approach to the study of febrile seizures and their consequences, has been published in high-impact journals and has been cited > 4000 times. In this renewal application, we embark on highly novel, bench-derived yet translatable solutions to a major human health problem.